Paternal exposure to certain exogenous agents, including recreational and therapeutic drugs, can adversely affect offspring viability, development and function. Morphine was one of the first drugs shown to have paternal-mediated consequences for offspring. They include physiological, endocrine and cognitive deficits and an altered pharmacological response to opioids. Pregnancy outcome and offspring viability are also adversely affected by paternal morphine exposure. In our previous studies with rats, a single morphine injection 24 hours before mating with a drug naive female was sufficient to reduce litter size, markedly increase neonatal mortality and enhance adult offspring sensitivity to analgesic effects of morphine. We also observed adverse effects of paternal morphine exposure on pre-implantation processes, litter sizes, and hormone levels in adult offspring using other treatment paradigms. The proposed project focuses on gender-specific endocrine deficits we previously observed in adult offspring of male rats chronically treated with morphine during adolescence. Our first aim is to more clearly define the nature of the effects on stress hormone levels in adult male and female offspring. Our second aim is to determine whether paternal exposure to morphine affects offspring fertility and/or the viability and endocrine status of males and females of subsequent generations. Our third aim will be to determine whether paternal exposure to morphine affects the reinforcing properties of morphine, a key component of its abuse liability, in adult offspring. Our final aim is to assess whether changes in "mu" or k opioid receptor homogeneity, binding properties or post receptor occupation translational processes are altered by paternal opioid exposure. Research on the effects of maternal exposure to exogenous agents on offspring viability and function has resulted in laws and educational programs to protect women and help them make more informed lifestyle decisions while pregnant. Research on the consequences of paternal exposure to exogenous agents however, particularly therapeutic and abused drugs like morphine, has been carried out only sporadically despite evidence of possible clinical significance and recent advancements in the identification of potential mediating mechanisms. As a result, the risks associated with paternal, compared to maternal, exposure to drugs like morphine are poorly understood and perhaps under appreciated. This is particularly troubling in view of the recent trend toward the increased use of prescription opioids and their diversion for illegal use. The current project could have clinical significance for a substantial number of individuals who's risk has largely gone unrecognized, children of opioid exposed fathers who may not have direct exposure to morphine or another opioid themselves. PUBLIC HEALTH RELEVANCE: Research on the consequences of paternal exposure to exogenous agents, particularly therapeutic and abused drugs like morphine and related opioids, has been carried out only sporadically over the past three decades despite evidence of possible clinical significance and recent evidence indicating the potential for epigenetic male germ line inheritance. This shortfall in our knowledge is particularly troubling in view of the recent trend toward the increased use of prescription opioids and their diversion for illegal use. The current project, which focuses on the effects of paternal-mediated effects of morphine, could have clinical significance for a substantial number of individuals who's risk has largely gone unrecognized, sons and daughters of opioid exposed fathers who may not have direct exposure to morphine or another opioid themselves.